Safety testing of metabolites: Expectations and outcomes.
Metabolites arising from chemical entities, old or new, are often mediators of toxicity. Frequently, metabolites are investigated in test animals, with the expectation that the resultant toxicity or activity will mimic the exposure of their formed counterparts. This communication described observations that showed discrepant kinetics between formed and preformed metabolites in the liver, intestine, and kidney, major drug removal organs. Differences in the observed areas under the curve (AUCs) or the extraction ratios (Es) of formed and preformed metabolites in the liver had been attributed to zonal, enzyme heterogeneity, membrane barriers, or transporters. Preformed and formed metabolite also differed in their handling by the kidney; only the preformed and not the formed metabolite would be filtered. In the intestine, differences in the absorption of the precursor and the metabolite and the flow pattern in the intestine would bring about discrepancy in the time-courses of the formed vs. preformed metabolites. Analytical solutions of the AUCs of the metabolites and extraction ratios, based on physiological modeling of the liver, kidney, and intestine, showed that the AUC of the preformed, administered metabolite was dependent only on metabolite parameters, whereas the AUC of the formed metabolite was modulated additionally by the metabolic, secretory and intestinal absorptive intrinsic clearances of the precursor drug. Hence, administration of the synthetic metabolite would not reflect the toxicity associated with the metabolite formed via bioactivation. However, data on preformed metabolite may be used for simultaneous fitting by a combined model of drug and metabolite. Such a strategy is shown to be successful in risk assessment of environmental chemicals. Upon refinement of the resultant model with data on metabolite transport and handling by modeling and simulations, the resultant model would be more robust to provide improved predictions on metabolite toxicity pursuant to drug administration.
Pang
K Sandy
KS
University of Toronto, Ontario, Canada. ks.pang@utoronto.ca
D000818:Animals; D019540:Area Under Curve; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000187:drug effects; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D010599:Pharmacokinetics; D018675:Toxicity Tests